Identification of BRCC3 and BRCA1 as Regulators of TAZ Stability and Activity.

TAZ (WWTR1) is a transcriptional co-activator regulated by Hippo signaling, mechano-transduction, and G-protein couple receptors. Once activated, TAZ and its paralogue, YAP1, regulate gene expression programs promoting cell proliferation, survival, and differentiation, thus controlling embryonic development, tissue regeneration, and aging. YAP and TAZ are also frequently activated in tumors, particularly in poorly differentiated and highly aggressive malignancies. Yet, mutations of YAP/TAZ or of their upstream regulators do not fully account for their activation in cancer, raising the possibility that other upstream regulatory pathways, still to be defined, are altered in tumors. In this work, we set out to identify novel regulators of TAZ by means of a siRNA-based screen. We identified 200 genes able to modulate the transcriptional activity of TAZ, with prominence for genes implicated in cell-cell contact, cytoskeletal tension, cell migration, WNT signaling, chromatin remodeling, and interleukins and NF-kappaB signaling. Among these genes we identified was BRCC3, a component of the BRCA1 complex that guards genome integrity and exerts tumor suppressive activity during cancer development. The loss of BRCC3 or BRCA1 leads to an increased level and activity of TAZ. Follow-up studies indicated that the cytoplasmic BRCA1 complex controls the ubiquitination and stability of TAZ. This may suggest that, in tumors, inactivating mutations of BRCA1 may unleash cell transformation by activating the TAZ oncogene.

Thoracolumbar Intervertebral Disk Extrusion in Dogs: Do Onset of Clinical Signs, Time of Surgery, and Neurological Grade Matter?

OBJECTIVE: The aim of this study was to determine the influence of time between the beginning of clinical signs, presentation and decompression, and combinations of several factors on the outcome and recovery of dogs undergoing surgery for thoracolumbar intervertebral disk extrusion (IVDE). STUDY DESIGN: In all, 433 client-owned dogs treated for IVDE between 2016 and 2020 were reviewed for signalment, neurological grade, rate of onset, duration of clinical signs, and surgical variables. Time from presentation to surgery was divided into three categories: S1 (0-12 hours), S2 (12-24 hours), and S3 (>24 hours). These variables were investigated to determine their influence on the return of pain sensation, urinary continence, ambulation and overall outcome. RESULTS: A significant association was found between an acute onset of clinical signs, worse neurological grade at presentation and poorer outcomes. There was a significant difference between S1, S2, and S3 in neurological grade at presentation (p < 0.001) and at discharge (p < 0.001); however, the latter was no longer significant when adjusted for the grade at presentation (p = 1,000). Disk fenestration was associated with a faster return to ambulation (p = 0.033). Duration of clinical signs and time of surgery did not correlate with the time to recovery and return of pain sensation, urinary continence, or ambulation. CONCLUSION: Dogs presented with severe neurological status and/or rapid onset of clinical signs were operated on more promptly, but their outcomes were also poorer. There was no significant evidence for a better outcome when surgery was not delayed.

Ultrasound-guided erector spinae interfascial plane block for spinal surgery in three cats.

CASE SERIES SUMMARY: The erector spinae plane (ESP) block consists of an interfascial injection of local anaesthetic between the erector spinae muscle group and the transverse processes of the thoracic vertebrae. This block targets the dorsal rami of the thoracic spinal nerves to desensitise the cutaneous area near the dorsal midline, the paraspinal muscles, the dorsal vertebral laminae and the facet joints. The purpose of this case series is to describe the perioperative analgesic effect and complications of ultrasound-guided ESP block with bupivacaine in three cats undergoing spinal surgery. Only one cardiovascular response was recorded in this case series. Just one cat received intraoperative rescue analgesia. Cats 1 and 2 recorded just one high pain score in the first 24 h postoperatively, and cat 3 recorded three high pain scores. The total amount of methadone given in the 24 h postoperatively was 0.6 mg/kg in cat 1, 0.9 mg/kg in cat 2 and 0.8 mg/kg in cat 3. All three cats suffered mild and transient intraoperative complications, which were easily addressed. There were no postoperative complications. RELEVANCE AND NOVEL INFORMATION: This case series documents a novel locoregional anaesthesia technique as an alternative to traditional systemic analgesia. The technique is part of a multimodal analgesia approach for spinal surgery in cats. Perioperative analgesic effect and complications presented in this case series are evaluated and discussed.

Retrospective evaluation of surgical outcomes after closure of durotomy in eight dogs affected by spinal subarachnoid diverticulum.

Background: Canine spinal subarachnoid diverticulum has been studied since 1968 and a few advancements have been made with regard to the treatment of this disease. Several surgical techniques have been proposed which include durectomy, fenestration, and/or marsupilization with the latter two regarded as the more favorable surgical treatments. Aim: In this retrospective study, we evaluated the closure of the durotomy incision in the treatment of canine spinal subarachnoid diverticulum. Methods: We retrospectively evaluated eight dogs with clinical signs and magnetic resonance imaging findings consistent with spinal subarachnoid diverticulum located in the cervical and thoracolumbar area. This was to determine whether the fenestration with closure of durotomy was superior to the marsupialization technique. In all dogs, fenestration and removal of subarachnoid adherences alongside closure of the durotomy were carried out. Results: Mild post-operative deterioration was observed in all dogs. Follow-up from 7 to 36 months indicated a satisfactory outcome. Conclusion: We conclude that the closure of durotomy has similar short-term and long-term outcomes compared to the previous reported studies. These results suggest that the closure of durotomy is a viable technique for spinal subarachnoid diverticulum.

Distribution of feline lymphoma in the central and peripheral nervous systems.

In cats, lymphoma (lymphosarcoma) is the most common neoplasm affecting the spinal cord and the second most common intracranial tumour. Although lymphoma commonly develops in the spinal cord as a part of a multicentric process, a primary form may occur. Lymphoma can exhibit a wide range of morphological patterns, including intraparenchymal brain mass, lymphomatosis cerebri, intravascular lymphoma, lymphomatous choroiditis and meningitis, extradural, intradural-extramedullary or intramedullary lymphoma in the spinal cord, or neurolymphomatosis in the peripheral nerves. Lymphoma may occur as a paraneoplastic disorder associated with peripheral neuropathies. Magnetic resonance imaging (MRI) and computed tomography (CT) are the techniques of choice for morphological assessment of nervous system lesions in vivo. However, biopsy should be performed to achieve a definitive diagnosis. Knowledge of the different morphological patterns expressed by lymphoma in the nervous system of cats allows veterinary clinicians to suspect lymphoma and to arrange appropriate diagnostic procedures, including immunophenotype and clonality studies, along with therapeutic protocols and prognostic evaluations.

Ascending haemorrhagic myelomalacia associated with systemic hypertension in a hyperthyroid cat.

CASE SUMMARY: An 8-year-old domestic shorthair neutered male cat was presented with acute onset of paraplegia, absent nociception on the pelvic limbs, tail and perianal area, and a previous history of uncontrolled hyperthyroidism (even after thyroidectomy) and chronic hypertension. The magnetic resonance findings (heterogeneous intramedullary ill-defined area, isointense on T1-weighted and hyperintense on short tau inversion recovery and T2-weighted scans between T12 and L5 spinal cord segments) were consistent with ascending haemorrhagic myelomalacia, which was confirmed by histopathology. It also revealed myelomalacia associated with diffuse arteriolar hyalinosis, similar to the reports found with hypertensive encephalopathy. RELEVANCE AND NOVEL INFORMATION: Myelomalacia should be considered as a possible outcome in cats with hypertension. Considering that hypertension is a common consequence of hyperthyroidism, emphasis should be given to blood pressure monitoring, especially after treatment of this condition. We describe the histopathological changes occurring in the spinal cord associated with a state of hypertension.

Canine and feline intracranial meningiomas: an updated review.

Meningiomas are the most common primary brain tumours in dogs and cats. There are several morphological phenotypes of this extra-axial neoplasm and they show predilections for certain anatomical locations. There have been a number of attempts to apply the current World Health Organization (WHO) classification for human meningiomas to dogs and cats and to obtain a universal classification scheme for domestic animals. Recently, certain enzymes involved in tumour growth have been recognised as biological markers and have been related to degrees of malignancy. The secondary effects of meningiomas have also been investigated, and vascular endothelial growth factor and peritumoural oedema have been reported to reduce survival rate. Breed and age predisposition are recognised in both dogs and cats and the presenting clinical signs are quite consistent. Magnetic resonance imaging and computed tomography are the techniques of choice for the presumptive diagnosis of meningiomas in domestic animals but advanced imaging techniques are constantly being developed and applied. Treatment methods for meningiomas involve a combination of de-bulking surgery, chemotherapy and radiotherapy, and detailed accounts of several treatment protocols have been reported.